Granulomas are the hallmark pathology associated with tuberculosis disease. These inflammatory lesions contain and eliminate bacilli and are the biological niche where mycobacteria proliferate and persist during active and chronic infection, respectively. One roadblock to the development of better tuberculosis treatments is the poorly understood biology of the granuloma compartment. T cell response is important to induce and maintain granulomatous immunity but factors of innate immunity also regulate these lesions. We have observed high levels of Vascular Endothelial Growth Factor (VEGF) produced by macrophages in mycobacterial granulomas, and shown that VEGF inhibition reduced the inflammatory response to infection without compromising control of bacteria. These data suggest the exciting possibility that VEGF inhibitors could lessen inflammation during tuberculosis disease. Several classes of inhibitors have already been tested by human clinical trials and are used in cancer therapies. Modulating granulomatous pathology is especially important since tuberculosis deaths are primarily a result of the overwhelming pathology that erodes lung and other organ function. The first aim of this proposal will test the hypothesis that cell death-induced release of ATP in the granuloma drives differentiation of VEGF-producing M2 macrophages, which stimulate the recruitment of new cells to repopulate the highly dynamic granulomas. In the second aim, we will measure the effects of VEGF inhibition on Mycobacterium tuberculosis (Mtb)-induced lung inflammation using pharmaceutical (clinically approved VEGF blockers) and genetically altered VEGF expression (LoxP-Cre mediated or transgene mediated). The effect of VEGF inhibitors will be tested on antibiotic control of the Mtb infection. We will test the hypothesis that local macrophage-induced VEGF recruits monocytes through their VEGR1 to the granulomas. In the third aim, we will develop novel macrophage- targeted VEGF blockers. Completion of these studies will lead to a better understanding of granulomatous disease pathogenesis and suggest whether a combined therapy of antibiotics and VEGF blockers could improve treatment of tuberculosis. Anti-VEGF therapies are already used in humans and the proposal will test whether their use may be extended to treat granulomatous diseases.